Esters of 1-substituted-3-disubstituted-pyrrolidinemethanols



United States Patent 3,479,370 ESTERS 0F 1SUBSTITUTED-3-DISUBSTITUTED- PYRROLIDINEMETHANOLS 'Carl D. Lunsford, Grover C. Helsley, and John A. Richman, Jr., Richmond, Va., assignors to A. H. Robins "Company, Incorporated, Richmond, Va., a corporation of Virginia No Drawing. Filed Aug. 8, 1966, Ser. No. 570,722 Int. Cl. C07d 27/04; A61k 27/00 U.S. Cl. 260326.3 18 Claims ABSTRACT OF THE DISCLOSURE Lower alkyl esters of 1-substituted-u,a-disubstituted-3- pyrollidinemethanols having pharmacological activity as analgeties are described.

The present invention relates to certain novel esters of substituted pyrrolidinemethanols and is more particularly concerned with the lower alkyl esters of 1-SubStltUt6d-a,ocdisubstituted-3-pyrrolidinemethanols, acid addition salts thereof, therapeutic compositions containing the same as active ingredients, and method of making and using them.

The invention is especially concerned with novel lower alkyl esters of 1substituted-a,a-disubstituted-3-pyrrolidinemethanols having the formula:

R O (LO-LE3 o wherein R is lower alkyl, phenyllower-alkyl, substituted phenyllower-alkyl, cycloalkyl, phenoxylower-alkyl, phenylaminolower-alkyl, phenyl and substituted phenyl,

wherein R is hydrogen, lower alkyl, phenyl, phenyllower alkyl, cycloalkyl and substituted phenyl,

wherein R is phenyl and substituted phenyl,

wherein R is lower alkyl,

and the pharmaceutically acceptable nontoxic acid addition salts thereof.

Prior art literature (U.S. Patent Numbers 2,833,775; 3,052,685; 3,068,237; 3,081,303; 3,153,946) discloses lsubstituted-a,a-disubstituted-2,3 and 4-piperidinemethanols. Van Campen et al. U.S. Patent 2,874,161 shows 1- substituted-a,a-disubstituted 2 piperidineethanols. Feldkamp et al. U.S. Patent 3,006,925 discloses l-alkyl-a,a-disubstituted-3-pyrrolidineethanols useful for muscular tremors and convulsion disorders. Various pharmacodynamic acivity has been claimed for the aforementioned piperidinemethanols and piperidineethanols. It has been found on the other hand, that the alcohol precursors of the novel esters of the present invention do not possess analgetic acivity, and in fact have not been found to have any pharmacological activity, and that the analgetic activity resides in the novel lower alkyl esters of the l-substituted-u,a-disubstituted 3 pyrrolidinemethanols of the present invention.

The l-substituted-u, x-disubstituted 3 pyrrolidinemethanol precursors will not possessing any demonstrable pharmacological activity are valuable as intermediates for the novel esters of the present invention and as intermediates for a series of pharmacologically active compounds disclosed in copending application entitled 3-Disubstituted Methylene Pyrrolidines.

The compounds of Formula I are primarily useful as analgetics. They were tested for analgetic activity by the method of Randall and Selitto, Arch. Inc. Pharmacodyn. 113, 233 (1957). When, for example, the propionate ester of l-ethyl-a-ethyl-a-phenyl 3 pyrrolidinemethanol was "ice tested, percent of all animals tested exhibited analgesia at a dose level of 30 mg./kg. LP. There were no observable side effects.

It is accordingly an object of the present invention to provide novel lower alkyl esters of 1-substituted-u,a-disubstituted-3-pyrrolidinemethanols useful for their analgetic activity. Another object is to provide novel compounds which when admiinstered to living animal bodies provide analgesia with minimum side effects. A still further object of the present invention is to provide methods for producing the novel lower alkyl esters of l-substituteda,a-disubstituted-3-pyrrolidinemethanols and methods for the utilization thereof. Additional objects will become apparent hereinafter and still others will be apparent to one skilled in the art.

In the definition of the symbols in the formulas hereof and where they appear elsewhere throughout this specification, the terms have the following significance.

A substituted phenyl radical is a phenyl radical substituted by any radical or radicals which are not reactive or otherwise interfering under the conditions of reaction, such radicals including lower alkoxy, lower alkyl, di-loweralkylamino, trifiuoromethyl, 'halo, and the like. The substituted phenyl radicals have preferably no more than one to three substituents such as those given above and, furthermore these substituents can be in various available positions of the phenyl nucleus and, when more than one substituent is present, can be the same or different and can be in various position combinations relative to each other. The lower alkoxy, lower alkyl and di-lower-alkylamino substituents each have preferably from one to four carbon atoms which can be arranged as straight or branched chains. A total of nine carbon atoms in all ring substituents, making a total of fifteen carbon atoms in the radical, is the preferred maximum.

The term lower alkyl as used herein includes straight and branched chain radicals of up to eight carbon atoms inclusive, preferably no more than six carbon atoms, and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl and the like. A lower-alkoxy group has the formula -0-loweralkyl.

The term cycloalkyl as used herein includes primarily cyclic radicals containing three up to nine carbon atoms inclusive and encompasses such groups as cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, methylcyclohexyl, propylcyclohexyl, ethylcyclopentyl, propylcyclopentyl, dimethylcyclohexyl, cycloheptyl, and cyclooctyl.

Included in the term phenylalkyl are lower-alkyl substituted monocarbocyclic aryl groups such as benzyl, phenethyl, methylbenzyl, phenpropyl and the like. Substituted phenylalky groups may contain all of the substituents and variations thereof already disclosed for a substituted phenyl radical. When halogen is referred to herein, preferably but not necessarily a halogen of atomic weight not greater than eighty is employed. A phenoxylower-alkyl radical has the formula phenyl-O-loweralkyl. A phenylamino alky 'has the formula phenyl- NH-lower-alkyl.

At least two asymmetric centers are present in many of the compounds which may be used in the present invention at the 3-position of the pyrrolidine ring and at the a-carbon atom. At least one pair of diastereoisomers therefore exists for each compound. Use of these diastereoisomers, or their optically active forms, is included within the scope of the present invention. The optically active forms of the diastereoisomers may be obtained by combining the basic racemic form with an optically active organic acid and separating by fractional crystallization the dand 1- forms.

This invention also includes acid addition salts of the above defined bases formed with nontoxic organic and inorganic acids. Such salts are easily prepared by methods known in the art. When the compounds are to be used as intermediates for preparing other compounds or for any other non-pharmaceutical use, the toxicity or nontoxicity of the salt is immaterial; when the compounds are to be used as pharmaceuticals, they are most conveniently used in the form of nontoxic acid-addition salts. Both toxic and nontoxic salts are therefore within the purview of the invention. The acids which can be used to prepare the preferred nontoxic acid-addition salts are those which produce, when combined with the free bases, salts whose anions are relatively innocuous to the animal organism in therapeutic doses of the salts, so that beneficial physiological properties inherent in the free bases are not vitiated by side-effects ascribable to the anions.

The base is reacted with the calculated amount of organic or inorganic acid in aqueous miscible solvent, such as ethanol or isopropanol, with isolation of the salt by concentration and cooling, or the base is reacted with an excess of the acid in aqueous immiscible solvent, such as ethyl ether or isopropyl ether, with the desired salt separating directly. Exemplary of such organic salts are those formed with maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic, acetic, propionic, tartaric, citric, lactic, malic, citraconic, itaconic, hexamic, p-aminobenzoic, glutamic, stearic acid and the like. Exemplary of such inorganic salts are those formed with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The starting materials for the novel compounds of the present invention are 1-substituted-3-cyanopyrrolidines and 1-substituted-Z-pyrrolidinones. The preparation of the 1-substituted-3-cyanopyrrolidines has been disclosed in copending application Serial No. 493,887, filed October 7, 1965. The 1-substituted-Z-pyrrolidinones are prepared by procedures well known in the art.

The compounds of the present invention are prepared by the following series of steps:

(1) A 1-substituted-3-cyanopyrrolidine of the formula RN-CHZCHCNCH2OH2 L (11) wherein R is as represented above, is reacted with an excess of a phenylmagnesium halide or a substituted phenylmagnesium halide of the formula R MgX wherein R is a phenyl radical or a substituted phenyl radical to give a 1-substituted-3-benzoylpyrrolidine or a 1-substituted-3-substituted benzoylpyrrolidine of the formula R-NOHzCH(COR )CHzOH (III) (2) The l-substituted-3-benzoylpyrrolidine or the 1- substituted-3-substituted benzoylpyrrolidine of the formula RN-CHzCH(COR )CHzOH (III) wherein R and R are as represented above is reacted (a) with an excess of a lower-alkyl-, phenyl-, phenylalkyl-, substituted phenyl alkylor a cycloalkyl magnesium halide of the formula or is (b) reduced by metal hydride reduction to give a 1 substituted-a,a-disubstituted-3-pyrrolidinemethanol of the formula RNOHzOH(CR R OH)OHzOH (1v) wherein R, R and R have the values given above.

(3) The l-substituted a,u-disubstituted-li-pyrrolidinemethanol (IV) is reacted with a lower aliphatic acid anhydride of the formula to give the novel lower alkyl esters of the present invention of the formula R wherein R, R R and R have the values given above. As an alternate procedure for preparing the novel compounds of the present invention a 1-substituted-2- pyrrolidinone of the formula RNCOCH2CH2CH2 wherein R is as represented above, is reacted with a ketone of the formula wherein R and R are as represented above in liquid ammonia in the presence of an alkali amide condensing agent to give a 1-substituted-2-oxo-a,wdisubstituted-3- pyrrolidinemethanol of the formula R-NCOOH(0R R 0H)CH2OH The 1 substituted-2-oxo-u,a-disubstituted-3-pyrrolidinemethanol (VI) is reduced by metal hydride reduction to give a 1-substituted-a,a-disubstituted-3-pyrroli dinemethanol of the formula Esterification of the 3-pyrrolidinemethanols (IV) by step (3) above gives the novel lower alkyl esters of the present invention of formula (I).

In the procedures involving the use of the Grignard reaction, the reactants are brought together in a suitable medium such as ether, benzene, toluene or dimethoxyethane, ether being the preferred reaction medium. The reactions are carried out for a period from about one hour to about eight hours and at a temperature from about room temperature to the reflux temperature of the solvent used. Sixhours appears to be the optimum reaction time when the reactions are carried .Out at refluxing temperatures. The cooled reaction mixtures are decomposed using aqueous ammonium chloride solution, the organic and aqueous layers separated and non-basic materials separated from the organic layers by acid-base extraction. The products are isolated by distillation at oil pump vacuum of the residual oil remaining after removal of the solvent.

Reduction of ketone groups as in the reduction of 3-benzoyl-l-ethylpyrrolidine or of amide groups as in the reduction of 1-(2-phenylethyl)-2-oxo-a,a-diphenyl-3- pyrrolidinemethanol is achieved by metal hydride reduction in a norganic solvent including, for example, ether, tetrahydrofuran, benzene, toluene, ethylene, glycol, dimethyl ether, methanol, isopropanol, and the like. Metal hydrides generally used include lithium aluminum hydride, sodium borohydride, potassium borohydride, sodium borohydride-aluminum chloride, diisobutylaluminum hydride and the like. The compound to be reduced is dissolved in or suspended in a solvent and the solution or suspension added dropwise to a stirred sus pension of the metal hydride in a solvent. After stirring and refluxing for about 2 to 5 hours, the reaction mixture is worked up and the product separated by procedures well known in the art.

In the alternate procedure the reaction between a 1-substituted-Z-pyrrolidinone and a ketone which can be a dialkyl ketone such as 2-b-utanone, an alkyl aryl ketone such as acetophenone, or a diaryl ketone such as benzophenone is carried out in liquid ammonia using an equivalent amount of an alkali amide as a metalating agent. Sodium amide, lithium amide and potassium amide prepared in situ can equally be used. After metalation of the pyrrolidinone a solution of the ketone in a suitable organic solvent such as ether, benzene, tolu ene, tetrahydrofuran and the like is added. After stirring for a period of about 1 to 3 hours, solid ammonium chloride is added to decompose the reaction complex with a suitable amount of solvent being added to replace the evaporated ammonia. The solvent is evaporated and the residue purified by crystallization if a solid or by distillation at oil pump vacuum if the prodnot is an oil.

The novel lower alkyl esters of the 1-substituted-a,adisubstituted-3-pyrrolidinemethan-ols are prepared from the precursor alcohols by reaction with a lower aliphatic acid anhydride in a solvent which provides a medium for but does not enter into the reaction. Solvents which can be used within the purview of this invention include benzene, toluene, Xylene and the like, benzene being the preferred solvent. Examples of lower aliphatic acid anhydrides include acetic anhydride, propionic anhydride, butyric anhydride and the like. The reactants are brought together in a suitable solvent as, for example, benzene, a catalytic amount of 2 pyridine added and the stirred reaction mixture refluxed for about five to twenty hours. The cooled reaction mixture is washed with aqueous sodium bicarbonate and water. The ester residue remaining after evaporation of the solvent is purified by distillaiton at oil pump vacuum or by crystallization of its acid addition salt from a suitable solvent.

PREPARATION OF INTERMEDIATES Preparation I: 3-benzoyl-l-ethylpyrrolidine An ethereal solution of phenylmagnesiurn bromide was prepared using 61 g. (2.5 moles) of magnesium, 410 g. (2.6 moles) of bromobenzene and 650 ml. of dry ether. The stirred ethereal solution was treated with 248 g. (2.0 moles) of 3-cyano-l-ethylpyrrolidine dissolved in an equal volume of dry ether and following addition the mixture was refluxed six hours. The reaction mixture was decomposed by the careful addition of a solution of 250 g. of ammonium chloride in 750 ml. of water. Following evaporation of the ether, the solution was heated on the steam bath to complete hydrolysis of the ketimiue. The product was extracted with ether and then separated from non-basic materials by acid-base extraction. The residual oil was distilled at 97-99 C./.05 mm. to give 180 g. (44%) of 3-benzoyl-l-ethylpyrrolidine.

Preparation II: 3 benzoyl-l-methylpyrrolidine To a stirred ether solution of phenylmagnesium bromide prepared from 37.5 g. (1.55 moles) of magnesium, 251 g. (1.60 moles) of bromobenzene and 425 ml. of dry ether was added dropwise a solution of 140 g. (1.27 moles) of 3-cyano-1-methylpyrrolidine in 200 ml. of dry ether. After refluxing two hours, the cooled reaction mixture was treated with a solution of 80 g. of ammonium chloride in 260 ml. of water. The ether was evaporated, the aqueous solution heated one hour to complete hydrolysis of the ketimine and the ketone product extracted with ether. Non-basic materials were separated by acid-base extraction. The residual oil after removal of the ether solvent was distilled in vacuo to give 102 g. (41%) of product at 93-95 C./.05 mm. Analysis: Calculated for C H NO: N, 7.40. Found: N, 7.57.

Preparation III: 1-benzyl-3-benz0ylpyrrolidine 1-benzyl-3-cyanopyrrolidine (279 g.; 1.5 moles) in 300 ml. of dry ether was added dropwise to stirred ether solution of phenylmagnesium bromide prepared from 73.0 g. (3.0 moles) of magnesium, 502 g. (3.2 moles) of bromobenzene in 550 ml. of dry ether. After a six hour reflux period the cooled reaction mixture was treated with a solution of 161 g. of ammonium chloride in 300 ml. of water. The ether was evaporated, the residual aqueous mixture heated one hour to complete hydrolysis and the organic material extracted with ether. After acid-base treatment to separate non-basic material, the residual basic material was distilled at 185190 C. to give g. (31%) of 1-benzyl-3-benzoyl-pyrrolidine.

Preparation IV Other l-substituted-3-benzoylpyrrolidines and l-substituted-B-(ring substituted benzoyl)-pyrrolidines prepared by the same method as above are disclosed below.

3-benzoyl-l-isopropylpyrrolidine is produced from 3- cyalno-l-isopropylpyrrolidine and phenylmagnesium brom1 e.

1-Benzyl-3-(p-chlorobenzoyl)-pyrrolidine is produced from 1-benzyl-3-cyanopyrrolidine and p-chlorophenylmagnesium bromide.

1-Benzyl-3-(p-trifluoromethylbenzoyl) pyrrolidine is produced from 1-benzyl-3-cyanopyrrolidine and p-trifluoromethylphenylmagnesium bromide.

1-Phenyl-3-(p-methoxybenzoyl)-pyrrolidine is produced from 3-cyano-l-phenylpyrrolidine and p-methoxyphenylmagnesium bromide.

1 Cyclohexyl-3-(p dimethylaminobenzoyl) pyrrolidine is produced from 1-cyclohexyl-3-cyanopyrrolidine and p-dimethylaminophenylmagnesium bromide.

l-(p-Tolyl) 3 (0 methylbenzoyl)-pyrrolidine is produced from 3-cyano-1-(p-tolyl)-pyrrolidine and p-methylphenylmagnesium bromide.

1-(2Phenoxyethyl) 3 benzoylpyrrolidine is produced from 3-cyano-1-(2-phenoxyethyl)-pyrrolidine and phenylmagnesium bromide.

1-[2- (N-Benzyl) phenylaminoethyl] -3-benzoylpyrrolidine is produced from 3-cyano-l-[2-(N-benzyl)-phenylaminoethyl]-pyrrolidine and phenylmagnesium bromide.

1-[2-(o-Tolyl)-ethyl]-3-benzoylpyrrolidine is produced from 3-cyano-1-[2-(o-tolyl)-ethyl]-pyrrolidine and phenyl-magnesium bromide.

Preparation V: l-ethyl-a-ethyl-a-phenyl-3-pyrrolidinemethanol In a 500 ml. three necked flask equipped with a stirrer. dropping funnel and efficient reflux condenser protected by a drying tube, were placed 6.1 g. (0.25 g. atom) of magnesium turnings, 50 ml. of dry ether and a crystal of iodine. After several milliliters of a solution of 39.0 g. (0.25 mole) of ethyl iodide in 50 ml. of dry ether was added, the reaction started and the remainder of the solution was added at a rate which maintained vigorous refluxing. After the addition was complete, stirring and refluxing were continued for one hour. To the stirred Grignard solution was added 30.4 g. (0.15 mole) of 3-benzoyll-ethylpyrrolidine in 50 ml. of dry ether at a rate which maintained gentle refluxing. Stirring and refluxing were continued for one hour. The cooled mixture was decomposed by the slow addition of a solution of 13.4 g. of ammonium chloride in g. of water. The ether layer was decanted into a separatory funnel and the pastey residue was extracted with three 100 ml. portions of ether. The combined ether extracts were washed with 10% sodium carbonate solution and then with water. After drying over sodium sulfate, the ether was distilled and the residue fractionated through a 10 cm. Vigreux column at .01 mm. The pale, yellow non-viscous oil boiled at 94-96 and weighed 18 g. (51% yield), 11 1.5254.

Analysis.-Calculated for C H NO: C, 77.20; H, 9.93; N, 6.00. Found: C, 77.23; H, 9.99; N, 6.12.

Preparation VI: Other 1substituted-a,a-disubstituted- 3-pyrrolidinemethanols In the manner of Preparation V, the following compounds are prepared:

l-Phenyl-a-ethyl-u-(p methoxyphenyl)-3-pyrrolidinemethanol from 1-phenyl-3-(p-methoxybenzoyl) -pyrrolidine and ethylmagnesium iodide.

l-Cyclohexyl-a-ethyl 0c (p-dimethylaminophenyl)-3- pyrrolidinemethanol from l-cyclohexyl 3 (p-dimethylaminobenzoyl)-pyrrolidine and ethylmagnesium iodide.

1-( p-Tolyl) -a-ethyl-a (o tolyl) -3-pyrrolidinemethanol from l-(p-tolyl) 3 (o methylbenzoyl)-pyrrolidine and ethylmagnesium iodide.

8 Preparation IX: 1-( Z-Phenylethyl)-2-oxo-a,-a-diphenyl- 3-pyrrolidinemethanol A liquid ammonia solution containing 0.293 mole of lithium amide was prepared by reacting 2.03 g. (0.293

1-(2-Phenoxyethyl)-a-ethyl-a-phenyl 3 pyrrolidine- 5 mole) of lithium metal with one liter of liquid ammonia methanol from 1-(2 phenoxyethyl)-3-bcnzoylpyrrolidine using a catalytic amount of ferric chloride. 1-(2-Phenyland ethylmagnesium iodide. ethyl)-2-pyrrolidinone (37.0 g.; 0.195 mole) was added 1 [2 (N Benzyl) phenylaminoethyl]-a-methy1-otslowly and the mixture. stirred one hour following addiphenyl 1,3 pyrrolidinemethanol from 1-[2-(N-benzyl)- tion. An ether solution of 35.5 g. (0.195 mole) of benzophenylaminoethyl]-3-benzoylpyrrolidine and methylmagphenone was added carefully and the resulting mixture nesium iodide. was stirred one hour. The reaction mixture was treated 1-[2-(0 Tolyl)ethyl]-a-ethyl-a-phenyl-3-pyrrolidincwith 16.04 g. (0.30 mole) of ammonium chloride with methanol from 1-[2-(o-tolyl)-ethyl]-3-benzoylpyrrolidine ether being added to replace the ammonia which evaporand ethylmagnesium iodide. 5 ated. Evaporation of the ether solution gave a 83.2% yield of product. The oily product was crystallized from Preparatlon VH1 y -p y -py isopropyl ether-isooctane to give white crystals melting at 110-111" C. Anal sis: Calculated for C H NO C, In a one liter three necked flask equipped With a Stir 80 83; H,6.78; N377 Found: C,80.54; Ni3.86 rer, dropplng funnel and efliclent reflux condenser protected by a drying tube, were placed 18.9 g. (0.50 mole) of lithium aluminum hydride and 400 ml. of dry ether. The suspension was stirred and a solution of 50.8 g. (0.25 Preparatlon 'P F Y YD' fl' p mole) of 1-ethyl-3-benzoylpyrrolidine in 200 ml. of dry Pyrrohdmemethanol ether was added slowly at a rate which maintained gentle refluxing. After the addition was complete, 80 g. of ethy 2 A solungngf (0135 F 9 of henylethyn' acetate was added at a rate which maintained vigorous 19 any pyn'ohdmelllethanol i anhydrous refluxing to decompose the excess amount of reducing tetrahydwfuran W added P e to a stlrred gently agent. The mixture was then cooled and 36 ml, of water refluxmg suslienslon of (0'15 mole) of hthlum was added slowly. The precipitated alumina was dissolved 3O t hydnde m anhydrous tetrajhydmfuran- The by the addition of 300 ml. of 25% sodium hydroxide soactlon mlxfure decomposed Water after a one lution. The ether layer was separated and the aqueous hour reaction Sodlum hydroxlde solutlon (50%) layer was extracted several times with ether. The comwas added to dlss?lve the alumma' The mixture was bined ether extracts were washed with water and the sol- Hired gh Cel te and the liltrate concentrated to an vent was evaporated. The residue was distilled at reduced 011 Whlch crystalhzed (n 9 The crud? yleld Y pressure and the fraction boiling at l08-109/ .005 mm. kecrxstalhzallon of the solld from was collected. The water-white, viscous oil weighed 40.1 Propyl ether gave mammal meltmg at 118-119 Analy' g (78% yield), 112415390. 81s: Calculated for C25H27NOI C,83.99; H,7.61; N,3.92.

Analysis.Calculated for 0 11 190: 0, 75.05; H, (348.146; 1147-66; 9 3. N 632 FoundZ c 7607. H, 933; N, 78 40 Thfi physical constants Of other 1-SI1bSt1tllted-a,a-dlSUbst1tuted-3-pyrrol1dinemethanols prepared as in Prepara- Preparation VIII: a-Methyl-a-phenyl-3-pyrrolidine- Hons are shown In Table methanol A solution of 129 g. (0.46 mole) of l-benzyl-a-methyl- Table I a-phenyl-3-pyrrolidinemethanol in 150 ml. of 95% ethanol was Placed in the reactlon bottle of the Fatalytlc reduc' Representative 1Substituted-a,u-disubstituted-3pyrrolition apparatus and 6 g. of 10% palladlum-on-charcoal dinemethanols catalyst was added. The mixture was heated at 70 C. and shaken with hydrogen until an equivalent of hydrogen was absorbed (about two hours). After cooling, the sus- R1 pension was filtered, and the solvent evaporated. The residue was distilled at reduced pressure and the fraction boiling at 111-113/ .02 mm. collected. The water-white, 4 viscous oil which solidified on cooling (M.P. 80100) weighed 52 g. (59% yield).

Analysis.Calculated for C12H17NOI C, 75.35; H, R 8.96; N, 7.32. Found: C, 75.18; H, 9.06; N, 7.37.

TABLE 1 Analysis B Pl (3 H N R R1 R (M.P.) 0. Calcd. Found Oalcd. Found Calcd. Found 06115 (110-111) 83.93 83.82 7.34 7.41 4.08 4.09 06m (81-82) 81.10 81.05 8. 24 8.25 4.98 4.79 c n. 147-9/. 01 81.31 81.21 8.53 8 53 4. 74 4.83 05115 (156-157) 80.59 80.58 7.56 7.56 5.53 5.62 05H. 132+134/. 01 79.07 78.94 9. 96 9.76 5.12 5.26 O5H5 (-78 75.35 75.30 8. 96 8. 83 7.32 7.61 0011. (66-67. 5) 80.86 80.88 7.94 7.86 5.24 5.41 0 11 (7981) 76.05 75.64 9.33 9.32 6.82 6.40 0611 91-93/.03 77.68 77.72 10.19 10.24 5.66 5.81 H c5115 147-148/. 01 81.31 81.16 8.53 8.36 4.74 4.81 p=ClC5H4 160-162/. 01 72.25 72.57 7.02 7.04 4. 44 4.39 CH3 p=CF3C8H4 96) 60.22 60.11 6.22 6.40 5.40 5. 44 CH3 =oF3oH4 -147/. 005 68.75 68. 86 6.35 6.56 4.01 3. 90 C2H5 p=(CH O)=C5H4 p=(CH5O)=C5H4 997-98) 73.87 74.05 7.97 8.01 4.10 4.05

The examples below illustrate in detail some of the compounds which comprise this invention and methods for their production. However, this invention is not to be construed as limited thereby in spirit or in scope. It will be apparent to one skilled in the art that numerous modifications in materials and methods can be adopted without departing from the invention.

Example 1 1 Ethyl-a,a diphenyl 3 pyrrolidinemethanol propionate hydrochloride To a solution of 12.82 g. (0.05 mole) of 1-ethyl-u,adiphenyl-3-pyrrolidinemethanol in 150 ml. of dry benzene was added 6.51 g. (0.05 mole) of propionic anhydride dropwise with stirring at room temperature. Stirred overnight at room temperature, then at 70 for 16 hours. The benzene was removed on a rotary steam evaporator at reduced pressure, then transferred to high vacuum to remove any unreacted anhydride. The remaining viscous oil was converted to the hydrochloride salt with ethereal HCl and recrystallized from ethyl ether and acetone, yielding white crystals; M.P. 168169 C. Analysis: Calculated for C H ClNO C,70.67; H,7.55; N,3.75; Cl, 9.48. Found: C,70.34; H,7.66; N,3.67; C1,9.51.

Example 2 1 Methyl a ethyl c phenyl 3 pyrrolidinemethanol propionate furmarate 1 Methyl a ethyl a phenyl 3 pyrrolidinemethanol propionate was prepared as in Example 1 in 86% yield. The colorless ester distilled at 102105 C./0.04 mm. A portion (5.5 g.; 0.02 mole) of the free base was added to a warm solution of fumaric acid (2.3 g.; 0.02 mole) in 40 ml. of isopropanol. After several minutes the warm solution was filtered and 100 ml. of isopropyl ether added to the clear filtrate. The colorless fumarate salt which separated weighed 6.0 g. (77% yield) after drying and melted at 112114 C. Analysis: Calculated for C H NO C,64.43; H,7.47; N,3.58. Found: C,64.l0; H,7.22; N,3.53.

Example 3.1-ethyl-a-benzyl-a-phenyl-3-pyrrolidinemethanol propionate fumarate 1 ethyl a benzyl a phenyl 3 pyrrolidinemethanol propionate was prepared in 94% yield by following the procedure described in Example 1. The fumarate salt was prepared by adding 11.0 g. (0.031 mole) of the free base to a warm solution of 3.6 g. (0.031 mole) of fumaric acid in 70 ml. of isopropanol, filtering the solution and adding 200 ml. of isopropyl ether to the clear filtrate. The crude fumarate salt weighed 10.7 g. (73% yield) and melted at 139142 C. The salt after recrystallization from isopropanol-isopropyl ether melted at 144-145.5 C.

Analysis.-Calculated for C H NO C, 69.36; H, 7.11; N, 3.00. Found: C, 69.65; H, 7.22; N, 2.98.

Example 4.-1-methyl-a-ethyl-a-phenyl-3-pyrrolidinemethanol acetate fumarate The methyl ester was prepared as in Example 1 from the precursor 1 methyl a ethyl-a-phenyl-3-pyrrolidinemethanole. The fumarate salt was prepared and recrystallized from 2-butanone-methanol to yield a colorless solid melting at 169172.5 C. The overall yield based on the starting alcohol was 69.3%. A neutral equivalent of 3.69 was found. The theoretical neutral equivalent is 3.77.

Example 5 .1-methyl-a-ethyl-a-pheny1-3-pyrrolidinemethanol butyrate In the same manner as given in Example 1, this compound is prepared by the reaction of l-methyl-u-methyl-uphenyl-3-pyrrolidinemethanol and butyric anhydride.

Example 6.1-phenylx-ethyl-a-(p-methoxyphenyl)- 3-pyrrolidinemethanol propionate In the same manner as given in Example 1, this compound is prepared by the reaction of l-phenyl-a-ethyl-a- (p-methoxyphenyl)-3-pyrrolidinemethanol and propionic anhydride.

Example 7.-1-cyclohexyl-u-(p-dimethylaminophenyl)- u-ethyl-3-pyrrolidinemethanol propionate In the same manner as given in Example 1, this compound is prepared by the reaction of l-cyclohexyl-a-(pdimethylaminophenyl)-a-ethyl-3-pyrro-lidinemethanol and propionic anhydride.

Example 8.1-(p-tolyl)-a-(o-tolyl)-a-ethyl-3 -pyrrolidinemethanol acetate In the same manner as given in Example 1, this compound is prepared by the reaction of 1-(p-tolyl)-a-(otolyl)-a-ethyl-3-pyrrolidinemethanol and acetic anhydride.

Example 9.1-(2-phenoxyethyl x-ethyl-a-phenyl-3- pyrrolidinemethanol acetate In the same manner as given in Example 1, this compound is prepared by the reaction of 1-(2-phenoxyethyl)- a-ethyl-u-phenyl-il-pyrrolidinemethanol and acetic anhydride.

Example 10.1-(2-phenylarninoethyl)-a-methyl-aphenyl-3-pyrrolidinemethanol acetate 1-[2 N-benzyl)phenylaminoethyl]-u-methyl-a-phenyl 3-pyrrolidinemethanol is reacted with acetic anhydride to give 1 [2 (N benzyl)phenylaniinoethyl]-a-methyl-3- a-phenyl-3-pyrrolidinemethanol acetate. Catalytic debenzylation of the latter compound using Pd/ C catalyst gives 1-(2 phenylaminoethyl) 0c methyl-a-phenyl-3-pyrrolidinemethanol acetate.

Example 11.1-benzyl-a-methyl-a-(p-chlorophenyl) 3-pyrrolidinemethanol acetate In the same manner as in Example 1, this compound is prepared by the reaction of l-benzyl-a-methyl-a-(p-chlorophenyl)-3-pyrrolidinemethano1 and acetic anhydride.

Example 12.1-benzyl-u-methyl-a-(p-trifiuoromethylphenyl)-3-pyrrolidinemethanol acetate In the same manner as in Example 1, this compound is prepared by the reaction of 1-benzyl-u-methylu-(p-trifluoromethylphenyl)-3-pyrrolidinemethanol and acetic anhydride.

Example l3.1-[2-(o-tolyl) ethyl]-a-ethyl-a-phenyl- 3-pyrrolidinemethanol acetate TABLE II Analysis B.P.m1n.

R2 R3 G.(M.P.) Calcd Found Calcd. Found Calcd. Found c n 02H. 90-92/. 02 73.53 73. 73 8.87 8.83 5.36 5.22

05H. CH3 (168. 5-172) 63.65 63.83 7. 21 7.21 3.71 3. 33

*The melting point and analysis are for the Iumarate salt.

Pharmacology TABLETS The high order of activity of the active agents of the Ingredients: Mg./tab.

present invention, as evidenced by tests in lower animals 1. Active ingredient, as salt 25.0 (representative of which are reported herein) is indi- 2. Corn starch 20.0 cative of utility in human beings as well. It will be clearly 3. Alginic acid 20.0 understood that the distribution and marketing of any 4. Sodium alginate 20.0 compound or composition falling within the scope of the 5. Magnesium stearate 1.3 present invention for use in human beings will of course Procedure: have to be predicated upon prior approval by govern- 25 1. Blend 1, 2, 3 and 4.

mental agencies, such as the Federal Food and Drug Administration, which are responsible for and authorized to pass judgement on such questions.

Formulation and administration: Effective quantities of any of the foregoing pharmacologically active compounds may be administered to a living animal body in any one of various ways, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The free basic amino compounds, while effective, are preferably formulated and administered in the form of their non-toxic acid-addition or quaternary ammonium salts for purposes of convenience of crystallization, increased solubility, and the like.

Although very small quantities of the active materials of the present invention, even as low as 0.1 milligrams, are effective when minor therapy is involved or in cases of administration to subjects having a relatively low body weight, unit dosages are usually five milligrams or above andpreferably twenty-five, fifty or one-hundred milligrams. Five to fifty milligrams appears optimum per unit dose, while usual broader ranges appear to be one to 500 milligrams per unit dose. The active agents of the invention may be combined with other pharmacologically active agents, or with buffers, antacids or the like, for administration and the proportion of the active agent in the compositions may be varied widely. It is only necessary that the active ingredient constitute an effective amount, i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed. Obviously, several unit dosage forms may be administered at about the same time. The exact individual dosages as well as daily dosages in a particular case will of course be determined according to established medical principles under the direction of a physician or veterinarian. Results upon administration of these novel materials have thus far proved extremely gratifying.

Examples of composition within the preferred ranges given are as follows:

CAPSULES Ingredients: Per Cap., mg. 1. Active ingredient, as salt 25.000 2. Lactose 146.000 3. Magnesium stearate 4.000 Procedure:

1. Blend 1, 2 and 3.

2. Mill this blend and blend again.

3. This milled blend is then filled into #1 hard gelatin capsules.

2. Add sufficient water portionwise to the blend from step #1 with careful stirring after each addition. Such additions of water and stirring continue until the mass is of a consistency to permit its conversion to wet granules.

3. The wet mass is converted to granules by passing it through the oscillating granulator, using 8-mesh screen.

4. The wet granules are then dried in an oven at 5 The dried granules are then passed through an oscillating granulator, using a IO-mesh screen.

6. Lubricate the dry granules with 0.5% magnesium stearate.

7. The lubricated granules are compressed on a suitable tablet press.

INTRAMUSCULAR INJECTION Ingredients: Mg. per ml. 1. Active ingredient, as salt 25.0 2. Isotonic buffer solution (q.s. to 2.0 ml.) 4.0 Procedure:

1. Dissolve the active ingredient in the buffer solution. 2. Aseptically filter the solution from step #1. 3. The sterile solution is now aseptically filled into sterile ampoules. 4. The ampoules are sealed under aseptic conditions. We claim: 1. A compound selected from the group consisting of lower alkyl esters of 3-pyrrolidinemethanols having the formula:

R 0 54145 I I.

wherein:

R is selected from the group consisting of lower alkyl of one to eight carbon atoms, phenyllower-alkyl, phenoxylower-alkyl, phenylamino-lower-alkyl, phenyl and X-phenyl,

R is selected from the group consisting of hydrogen,

lower-alkyl of one to eight carbon atoms, phenyllower-alkyl, phenyl and X-phenyl,

R is selected from the group consisting of phenyl and X-phenyl,

R is lower alkyl of one to eight carbon atoms inclusive,

and wherein X is selected from the group consisting of from 1 to 3 of the following radicals: lower-alkoxy, lower alkyl, di-lower-alkyl amino, trifluoromethyl, halogen and acid addition salts thereof.

2. A compound of claim 1 which is a lower alkyl ester having one to eight carbon atoms of 1-ethyl-a,a-diphenyl- 3-pyrrolidinemethanol.

3. A compound of claim 1 which is a lower alkyl ester having one to eight carbon atoms of l-ethyl-a-ethyl-aphenyl-3-pyrrolidinemethanol.

4. A compound of claim 1 which is a pharmaceutically acceptable acid addition salt of a lower alkyl ester of l-lower alkyl-a-lower alkyl-a-phenyl-3-pyrrolidinemethanol wherein lower alkyl has 1-8 carbon atoms.

5. A compound of claim 1 which is a pharmaceutically acceptable acid addition salt of a lower alkyl ester of 1- lower alkyl-a-lower alkyl-a-substituted phenyl-3-pyrrolidinemethanol wherein lower alkyl has 1-8 carbon atoms.

6. A compound of claim 1 which is a lower alkyl ester of l-lower alkyl-a-lower alkyl-a-phenyl-3-pyrrolidinemethanol where in lower alkyl has 1-8 carbon atoms.

7. A compound of claim 1 which is a lower alkyl ester of l-lower alkyl-a-lower alkyl-a-substituted phenyl-3-pyrrolidinemethanol wherein lower alkyl has 1-8 carbon atoms.

8. A compound of claim 1 which is l-ethyl-a-ethyl-aphenyl-3-pyrrolidinemethanol propionate.

9. A compound of claim 1 which is l-ethyl-a-phenyl- 3-pyrrolidinemethanol propionate,

10. A compound of claim 1 which is l-benzyl-a-phenyl- 3-pyrrolidinemethanol propionate.

11. A compound of claim 1 which is l-methyl-amethyl-a-phenyl-3-pyrrolidinemethanol propionate.

12. A compound of claim 1 which is l-methyl-a-ethyla-phenyl-3-pyrrolidinemethanol propionate fumarate.

13. A compound of claim 1 which is l-ethyl-a,a-diphenyl-3-pyrrolidinemethanol propionate hydrochloride.

14. A compound of claim 1 which is l-isopropyl-aethyl-u-phenyl-Il-pyrrolidinemethanol propionate.

15. A compound of claim 1 which is l-ethyl-a-ethyhaphenyl-3-pyrrolidinemethanol acetate.

16. A compound of claim 1 which is l-methyl-a-ethyla-phenyl-3-pyrrolidinemethanol propionate fumarate.

17. A compound of claim 1 which is l-ethyl-a-benzyla-phenyl-3-pyrrolidinemethanol propionate fumarate.

18. A compound of claim 1 which is l-methyl-u-ethyla-phenyl acetate fumarate.

References Cited Doyle et al.: Chemical Abstracts, vol. 56, pp. 1425- 26 (1962).

ALEX MAZEL, Primary Examiner JOSE TOVAR, Assistant Examiner US. Cl. X.R. 

